The Vietnam Era Twin Study of Aging (VETSA) study provides a unique opportunity to examine genetic and environmental influences on early cognitive change and associated risk factors. In VETSA 2, we propose our first 5-6 year follow-up of a large, age-homogenous sample that was middle-aged (50s) at baseline. Longitudinal studies of cognitive aging have employed cohort-sequential designs with age-heterogeneous samples that are usually weighted toward older subjects. There is solid evidence of change in midlife to early old age, but because mean change does tend to be modest, increased ability to examine individual differences is key. While no single design can provide all the answers, our novel design does enhance the ability to study differences in within-individual change patterns. By focusing on midlife, our design also has increased potential to identify early predictors of cognitive decline. Moreover, we are including an objective measure of allocation of cognitive effort that will be an important indicator, even in the absence of performance changes. We will follow 720 middle-aged twin pairs (1440 individuals) 5-6 years after collection of baseline neurocognitive, biomedical, and psychosocial data. Mean age at our VETSA 2 follow-up will be 60 (57-66). Applications from 2 Principal Investigators (Kremen, UCSD;Lyons, Boston Univ.) comprise a single integrated project. Our focus is to characterize genetic and environmental influences on early age-related changes in cognitive effort and performance (Aims 1, 2), and to examine major factors that mediate or moderate those changes: APOE [Aim 3];other biomedical risks [Aim 4];lifestyle/psychosocial factors [Aim 5]). Aims are: 1) Characterize genetic and environmental influences on cognitive change over time (and specific component processes driving change);2) Investigate cognitive efficiency (i.e., ratio of performance to effortful resource allocation [based on task-evoked pupillary responses]) as a key cognitive aging process;3) Examine the relationship of APOE genotype to changes in cognitive function over time;4) Elucidate biomedical risk factors related to cognition and identify specific health risk factors that best predict cognitive aging (with multivariate genetic models not previously used);5) Examine lifestyle and psychosocial factors related to cognitive aging. We will obtain comprehensive assessments in multiple domains, utilize a novel approach that integrates the twin method with experimental/neuroscience approaches of parsing cognitive component processes, and use a cost-effective psychophysiological method (pupillometry) to measure cognitive effort. PUBLIC HEALTH RELEVANCE: VETSA 2 builds upon the unique resource of VETSA 1 and creates an invaluable resource for the study of change from midlife (an under-studied area) to early old age, and for understanding the interplay of biological and environmental factors that are key early predictors of declining or successful aging. The VETSA 2 project builds upon the unique resource of VETSA 1 and creates an invaluable resource for the study of midlife (an under-studied area) and for understanding the interplay of biological and environmental factors that are key determinants of successful aging.